Abstract Project 4: Photodynamic therapy (PDT) can produce local ischemia during illumination that leads to treatment-limiting hypoxia. Ischemia and hypoxia can limit direct cytotoxicity, as well as alter other aspects of PDT response, for example, effects on signal transduction and immune responses have been documented. Thus, tumor microenvironment during illumination is critical to multiple facets of PDT response that collectively determine therapeutic efficacy. Preliminary data from our clinical trial of pleural-PDT (p-PDT) for mesothelioma detect response-altering ischemia during illumination. P-PDT did not control local recurrence, despite improvement in survival, which could indicate microenvironment-induced limitations in cytotoxicity. In agreement, we measured decreases in local concentrations of total and oxygenated hemoglobin during illumination, respectively indicating treatment-induced ischemia and hypoxia. Furthermore, the addition of surgery to PDT could alter microenvironment because surgery induces the systemic release of pro-inflammatory and vasoactive cytokines. In particular, we found IL-6 induction by surgery to correlate with hypoxia development in thoracic tissues during their subsequent illumination. From these data, we hypothesize that vascular response to intraoperative PDT of the mesothelioma-involved thoracic cavity will determine treatment outcome. Studies will be performed as a part of our Phase II, p-PDT trial, as well as in murine models of intrathoracic and intraoperative PDT. Aim 1 will ascertain the vascular microenvironment of mesothelioma in patients and evaluate the clinical relevance of procedure-induced hemodynamic change. Our goals include assessment of the vascularization of mesothelioma; measurement of PDT-induced changes in vascular function; and definition of how these factors correlate with local control, toxicities, and survival in p-PDT. Aim 2 will determine how vascular responses contribute to the efficacy of intraoperative PDT in murine models of mesothelioma. This Aim will define the consequences of thoracic illumination and surgery-induced cytokine signaling on vessel response to PDT, the importance of this damage to outcome, and the potential to modulate vascular response during p-PDT for therapeutic benefit.